Cognitive deficits as well as positive and negative symptoms in schizophrenia may arise from abnormalities in very basic processes of detecting and encoding stimuli in appropriate neural circuitry. Those processes can be monitored with event-related potentials (ERPs), EEG oscillations and fMRI activation. Abnormalities have been reported repeatedly in schizophrenia in multiple auditory cortical ERPs and in theta and gamma EEG rhythms associated with deviance and novelty detection, as well as with encoding and retrieval of episodic and working memory. As described in Subprojects 0001 and 0003, our CCNMD has found that in schizophrenia gamma oscillatory abnormalities correlate with abnormal fMRI BOLD responses, including those in superior temporal gyrus and hippocampus. The microcircuits generating gamma and theta rhythms in neocortex and hippocampus have been elucidated in recent years. In both brain regions, the microcircuits are similar and consist of glutamatergic projection neurons reciprocally connected with one or more types of GABAergic interneurons. We propose that in schizophrenia hypofunction of glutamatergic input to GABAergic interneurons occurs in theta and gamma microcircuits with consequent GABAergic hypofunction leading to abnormal oscillations in the circuits. Our studies have identified factors in schizophrenia that could lead to glutamatergic and GABAergic dysfunction in hippocampal and cortical brain regions, including abnormal dysbindin expression and abnormal activation of NMDA receptors and the neuregulin 1-erbB4 signaling pathway. Subproject 0007 will test hypotheses related to these findings and potential consequences for glutamatergic-GABAergic neurotransmission. Aim 1 will examine whether or not presynaptic factors that contribute to glutamatergic function of theta and gamma microcircuits are abnormal in schizophrenia and a dysbindin mutant mouse (sandy). Aim 2 will use a novel neurochemical stimulation paradigm in human postmortem tissue and a Gsa overexpressing mouse to examine NMDA receptor function and NMDAR-dopamine receptor interactions that may contribute to theta and gamma microcircuit dysfunction in schizophrenia. Aim 3 will examine whether markers of GABAergic transmission are in fact altered in the gamma and theta microcircuits in that disorder.